All posts by Dr. Chris

Pediatrician trained at University of Michigan Medical School, University of Hawaii and University of Chicago for residencies. Spent 20 years at the Commonwealth Health Center in Saipan, CNMI, before establishing Ebert Children's later Ebert Family Clinic in Frisco, CO in 2000. Published in the Journal of High Altitude Medicine and Biology
Acclimation, Altitude Science, Athletic Training, Health, High Altitude, High Altitude Training & Fitness

KYRGYZSTAN VS SUMMIT COUNTY, COLORADO: EXERCISE AT ALTITUDE

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How does the low oxygen environment at altitude affect our ability to exercise?  What is the risk for developing harmful changes in the heart and lungs? Does sleep apnea contribute to these risks? Can supplemental oxygen reverse or reduce these risks and increase our exercise ability at altitude?

An audience of conference participants sit observing a slide in a presentation reading "Cardiac function and PH in 97 Kyrgyz Highlander and 76 Lowlander (50% women).

These important questions have been studied by an international research team conducting tests on residents of the Tien Shan mountain range in Kyrgyzstan, 2500-3500 m (8,200 to 11,482 feet). Dr. Silvia Ulrich presented some of their findings at the Hypoxia 2025 conference in Lake Louise in the Canadian Rocky Mountains this past winter. Using an exercise bike they measured ECG, pulmonary gas exchange and oxygen saturation in healthy highlanders. Participants’ average age was 48 years, 46 % were women, and their average oxygen saturation (SpO2) at rest was 88%. Normal occupations include nomadic herdsmen, hunters and soldiers who usually travel by car or horse, with no prior experience cycling or running. An echocardiogram was performed to assess pulmonary artery pressures (PAP) and right heart function.

Arterial blood gas analysis at baseline showed a normal pH, low oxygen, mildly decreased carbon dioxide and bicarbonate, and higher hemoglobin concentrations. Bicarbonate values were 22-26 moles/L. In Summit county, in the Rocky Mountains of Colorado, with residents living between 2500 to 3300 m bicarbonate values are 17-20 moles/L.

Results showed their peak oxygen uptake, and peak work rate was reduced by one quarter compared to predicted values for lowlanders. Oxygen saturation decreased during exercise. “Exercise limitation was related to an exercise -induced worsening of hypoxemia, high ventilation equivalents for oxygen uptake and carbon dioxide output, a reduced external work efficiency and a lower peak heart rate than predicted for age.” (1) In other words, they had to breathe harder to maintain their oxygen and carbon dioxide at normal values and use more effort for the same musculoskeletal output. Their heart rate did not increase as much as a person from lower altitude doing the same work.

There is little research on exercise capacity in long-term residents at altitude.  Most studies focus on athletes or comparing healthy acclimatized men to recent arrivals. The hypoxic environment is a known risk for pulmonary hypertension, which can lead to exercise intolerance and fatigue that is reversible with descent or oxygen use when diagnosed in a timely manner. Sleep apnea with the accompanying hypoxic episodes adds to this risk. Summit County residents show improvement in both systemic and pulmonary hypertension with supplemental oxygen during sleep, according to local health care providers.

Kyrgyzstan residents studied showed a strong correlation between  the incidence of sleep apnea with hypoxia (time below 90% SpO2), and abnormal pulmonary artery pressures. Echocardiograms compared 97 highlanders with 76 lowlanders who were asymptomatic. Between 6% and 35% had increased PAP depending on which definition is used. 

A slide at a conference presentation on the effect of high-dose SOT on pulmonary artery pressures and cardiac output in highlanders at risk for PH at 3250 meters.

The research team also evaluated their response to supplemental oxygen at altitude and 760m elevation using the six minute walk test. Although the test subjects reported less shortness of breath and had higher measured oxygen levels they were not able to walk further. Supplemental oxygen did reduce pulmonary artery pressures in those at risk when tested at 3,200 m.

A slide from a presentation on an experiment where oxygen levels in residents of high altitude in Kyrgyzstan are measured during a 6-minute walk.

This research was conducted by a crew of scientists who brought all the equipment with them to a basic medical clinic in a village. These measurements and much more are performed on a daily basis at the St. Anthony Summit Hospital, a 34-bed hospital serving five counties in Colorado, located at 2800 m. A parallel study to establish baseline normal values for the healthy population and identify the risk for pulmonary hypertension in asymptomatic mountain residents would be valuable for health care providers who are frequently asked to counsel residents on the risk of living at altitude.

References

Forrer A, Scheiwiller PM, Mademilov M, Lichtblau M, Sheraliev U, Marazhapov NH, Saxer S, Bader P, Appenzeller P, Aydaralieva S, Muratbekova A, Sooronbaev TM, Ulrich S, Bloch KE, Furian M. Exercise Performance in Central Asian Highlanders: A Cross-Sectional Study. High Alt Med Biol. 2021 Dec;22(4):386-394. doi: 10.1089/ham.2020.0211. Epub 2021 Aug 24. PMID: 34432548.

Lichtblau M, Saxer S, Furian M, Mayer L, Bader PR, Scheiwiller PM, Mademilov M, Sheraliev U, Tanner FC, Sooronbaev TM, Bloch KE, Ulrich S. Cardiac function and pulmonary hypertension in Central Asian highlanders at 3250 m. Eur Respir J. 2020 Aug 20;56(2):1902474. doi: 10.1183/13993003.02474-2019. PMID: 32430419.

Altitude Science, COVID-19, Doc Talk, Health, High Altitude, Medicine, Pandemic

COVID-19 and Altitude: A discussion about the research with Dr. Isain Zapata

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Early in the pandemic, researchers were eager to learn more about the COVID-19 virus and how it takes shape in different communities. One area of particular interest for some of those researchers was the relationship between COVID-19 and high altitude, as altitude has been shown to impact other chronic diseases like COPD1, lung cancer2, and cardiovascular disease3. However, many of the early studies that were conducted resulted in nonspecific findings or trends in data that could be better explained by different variables than solely altitude. 

For example, one of the preliminary studies conducted in Colombia analyzed positive cases, deaths, and case fatality rates in 70 different municipalities ranging from 1 to 3180m above sea level. What these researchers found was that there was a negative correlation between altitude and COVID-19 case fatality rates4, meaning there were less COVID-19 deaths at higher altitude when compared to those at low altitude. One thing that is mentioned by the researchers is that population density plays an important role in the transmission of this virus4. The researchers concluded that this negative correlation seen between altitude and COVID-19 fatalities could be better explained by the differences in population in the varying locations4. 

Another early study conducted in 2020 looked at around 4 months of data in the U.S and around 2 months of data in Mexico and found that U.S. communities living at >2000m elevation had higher mortality rates than those at <1500m5. In Mexico, individuals <65 years old, the risk of death due to COVID-19 was 36% for those living at >2000m when compared to those living at <1500m5.

We discussed some of these findings with Dr. Isain Zapata, who is one of the authors of the article “Revisiting the COVID-19 fatality rate and altitude associated through a comprehensive analysis”. Which was a study conducted by a group of researchers at Rocky Vista University that further investigated the relationship between altitude and COVID-19 fatalities. Dr. Zapata said that some of their motivation to look further into this relationship was due to the lack of consistency in the conclusions formed by many of the studies conducted early in the pandemic. He hypothesized that there could be a few reasons for these inconsistencies, one being that there is a large discrepancy over what level of elevation is considered “high altitude” and another being that many of the studies published early on were specific to a certain location. Lastly, these studies were solely looking at data from the first few months of the pandemic, when COVID-19 infections were just beginning to take form. 

In their study, this group of researchers looked at COVID-19 fatality data from March 2020 to March 2021 in the mountain region of the western United States, including Montana, Idaho, Wyoming, Nevada, Utah, Colorado, Arizona, and New Mexico. Within each state, they looked at the data specific to each county and then subdivided them into census blocks6. Then determined the weighted average of the block’s altitude and adjusted for population density6. 

They found that in Colorado, Idaho, and Wyoming, communities living at higher altitude had lower COVID-19 fatality rates6. This trend was also observed when they performed a meta-analysis of all of the data from the U.S. Mountain region6. However, when looking at Arizona, Montana, Nevada, and Utah individually, there was not a significant relationship observed between high altitude and COVID-19 mortality6. One of the points discussed by the researchers is that in these states, the discrepancy may be based on the population density6. In Arizona and Nevada, the majority of the population in that state live at lower altitudes6. The researchers also discuss that the size of the state and the number of counties in each state may also play a role in these trends6. 

They also found that in Arizona, Colorado, Idaho, and Wyoming, areas with higher median incomes were associated with lower COVID-19 fatality rates6. 

The researchers observed that in New Mexico, there was a reverse altitude effect, in which, there was higher mortality rates at higher altitudes6. There was also a higher associated risk across the whole mountain region for the Native American population6. One observation that was pointed out in the discussion section of this article, is that New Mexico has one of the highest Native American populations6. In addition, Native Americans have been shown to have higher incidence of developing chronic diseases that are associated with worse COVID-19 fatality rates6. 

So, what does this all of this mean? Overall, in the U.S. western Mountain region, there were fewer Covid-19 deaths for communities living at higher altitude when compared to those living at lower altitude6. This same trend was observed when just looking at the data for Colorado6. 

Another point that was discussed by the researchers is that these implications can likely be explained by both protective physiologic changes that occur at altitude as well as demographic trends6. The demographic trend may be hypothesized to be a result of people who choose to live in areas of higher altitude as they are often seeking more active lifestyles. The results of this study leave room for more research to be conducted on how our bodies physiology changes in order to adapt to life at higher altitudes.  

  1. Andreas Horner et al., “Altitude and COPD Prevalence: Analysis of the Prepocol-Platino-Bold-Epi-Scan Study,” Respiratory Research 18, no. 1 (August 23, 2017), https://doi.org/10.1186/s12931-017-0643-5.
  2. Kamen P. Simeonov and Daniel S. Himmelstein, Lung Cancer Incidence Decreases with Elevation: Evidence for Oxygen as an Inhaled Carcinogen, November 12, 2014, https://doi.org/10.7287/peerj.preprints.587v2.
  3. Martin Burtscher, “Effects of Living at Higher Altitudes on Mortality: A Narrative Review,” Aging and Disease, 2014, https://doi.org/10.14336/ad.2014.0500274.
  4. Eder Cano-Pérez et al., “Negative Correlation between Altitude and Covid-19 Pandemic in Colombia: A Preliminary Report,” The American Journal of Tropical Medicine and Hygiene 103, no. 6 (December 2, 2020): 2347–49, https://doi.org/10.4269/ajtmh.20-1027.
  5. Orison O. Woolcott and Richard N. Bergman, “Mortality Attributed to Covid-19 in High-Altitude Populations,” High Altitude Medicine &amp; Biology 21, no. 4 (December 1, 2020): 409–16, https://doi.org/10.1089/ham.2020.0098.
  6. Carson Bridgman et al., “Revisiting the Covid-19 Fatality Rate and Altitude Association through a Comprehensive Analysis,” Scientific Reports 12, no. 1 (October 27, 2022), https://doi.org/10.1038/s41598-022-21787-z. 
Acclimation, Acetazolamide, Altitude Science, Child Growth & Development, Diamox, Doc Talk, Health, High Altitude, Medicine, Sleep at Altitude

Sharing at the Chateau: 23rd International Hypoxia Symposium in Lake Louise

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I attended the 23rd International Hypoxia Symposium in Lake Louise, Canada to present some of the research on altitude I’ve been conducting in Colorado. The conference has been going on since 1979, and for the past 26  years the organizers have been Robert Roach and Peter Hackett, world-renowned medical researchers from Colorado. Meeting most of the famous altitude researchers from all over the world was an inspiration.  Personal talks and sharing information were equally important to imbibing the latest knowledge about hypoxia and hemoglobin.

A slide is projected onto a screen over the heads of conference participant, depicting statistics showing infant birthweight in mammals decreasing over increasing elevations.
From Jay Storz’s presentation at the 2025 International Hypoxia Symposia in Lake Louise, Canada

Antarctic Icefish: Life Without Hemoglobin, was presented by Kristen O’Brien, expanding the concept of oxygen distribution in living beings and introducing us to varieties of fish we have never heard of. Her talk was followed by our “Mice and Men” guy, Jay Storz (and colleague Graham Scott), who along with Jon Velotta mentioned in our blogpost on the show “This Podcast Will Kill You” collect the large eared deer mice from peaks such as Blue Sky Mountain to study adaptation to hypoxia in their labs. The talk recognized for first prize was on Altitude Headaches, including a discussion of migraines, by Andrew Charles.

Every evening there was a banquet and speaker.  Astronaut Jessica Meir spent 210 days aboard the space station.  She shared a wide range of challenges such as exercising without gravity, choosing a compatible crew, getting boxes of treats from home, and effects of prolonged weightlessness on your eyes and muscles.

A slide projected onto a conference room screen before participants depicts results for six minute walks on and off oxygen.
Silvia Ulrich presented on Pulmonary Circulation of Central Asian Highlanders at the 2025 International Hypoxia Symposium at Lake Louise, Canada.

The research I would like to see duplicated in Summit County was from Kyrgyzstan, where Silvia Ulrich studied the hearts and lungs of the permanent residents at 9000 feet using the six minute walk as one of her tools.  They did not score higher when studied at sea level! She ran tests for pulmonary hypertension, which could be important here.

Of course, there was a talk on Sleep Disordered Breathing (sleep apnea) by Esther Schwarz, something we pay a great deal of attention to in our own clinic in Frisco, Colorado and have several research projects on the improvement we see with supplemental oxygen. The role of mitochondria in cellular function in hypoxia was presented by Dr. Christian Arias-Reyes, a researcher at Seattle Children’s Hospital who is originally from La Páz, Bolivia.  I met him at the Chronic Hypoxia conference in 2019 when he was a graduate student in Quebec and again in La Páz at this year’s conference. 

A line of people pose in front of a cafe with signs and plants hanging above a stone-tiled street lined with buildings
Altitude experts Dr. Zubieta Calleja, Dr. Christian Arias-Reyes, Dr. Michele Samaja and Dr. Christine Ebert-Santos with colleagues of the Hypoxia Symposia in front of a pizzeria in Coroico, Bolivia.

A deep dive into how our neurons react to hypoxia in the brain by releasing nitric oxide to dilate blood vessels and preserve circulation reenforced the counseling I do here in my clinic to parents whose children have breath holding spells or babies with dips in their oxygen on home monitors. Along with all the millions of children and adults living at 12,000 feet in Bolivia, we can witness that hypoxia does not cause brain damage. (Not to be confused with anoxia, a complete lack of oxygen.)

Lastly, Nobel prize winner and fellow pediatrician Gregg Semenza spoke on research to find a blocking compound against HIF- hypoxia inducible factor, as a cure for some cancers. Gregg’s work was described in our blog on the Nobel prize being awarded to scientists working on hypoxia. HIF deserves its own blogpost! More about cancer and hypoxia at altitude from the Chronic Hypoxia Conference in La Páz.

I was selected to give my presentation, “Colorado Kids Are Smaller” to both conferences. I have been working on this for 20 years. You can read more on our blog where it is titled “Mountain Kids Are Smaller”.  My goal is to get a unique growth chart for children under age two at altitude, to save parents and providers anxiety and money trying to get our kids to “be the same” as those at sea level.

The most useful tidbit of information came on the bus ride back to Calgary. Dr Heimo Mairbaurl, PhD shared that a quarter dose of acetazolamide was sufficient for his acute mountain sickness symptom prevention, 62 mg for a guy over 6 feet tall. Although there was a study on a new possible preventive treatment, prochlorperazine, done on Mount Blue Sky last fall, I still swear by the old drug formerly known as “Diamox”.

Acclimation, Altitude Science, Child Growth & Development, Doc Talk, Genetics, Health, High Altitude

The Frisco Score: A New Tool for Diagnosing HAPE

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by Madison Palmiero, PA-S

While HAPE may be a run-of-the-mill diagnosis for providers with years of experience practicing at altitude, it can be less straightforward for those who are unfamiliar with the condition. There are currently three recognized categories of HAPE. Classic HAPE (C-HAPE)  occurs when someone who resides at low altitude travels to high altitude and develops pulmonary edema. Re-entry HAPE (R-HAPE) occurs when high altitude residents travel to low altitude, then return to high altitude. High-altitude resident pulmonary edema (HARPE) occurs in high altitude residents without a change in altitude. HARPE is often brought on by an upper respiratory tract infection. 

HAPE and pneumonia can have similar presentations including shortness of breath, cough, fatigue, and malaise. Patients with either condition may have decreased oxygen saturation levels and abnormal findings on chest radiography. In response to this phenomena, Dr. Chris Ebert-Santos of Ebert Family Clinic in Frisco, Colorado (9000′) and Sean Finnegan, PA-C set out to develop a scoring system to differentiate the two diagnoses. If providers could easily differentiate between pneumonia and HAPE, this would shorten the time from presentation to diagnosis and would avoid unnecessary antibiotic use.

Dr. Chris and Sean Finnegan, PA-C summarized their research findings into a scoring system named the “Frisco Score”. They analyzed data from St. Anthony Summit Medical Center and associated clinics at or above ~2,760 meters above sea level from January 1, 2018 to May 30, 2023. The study looked at patients under the age of 19 who presented with hypoxemia or other respiratory concerns and had a chest x-ray performed and oxygen saturation measured. The final case review consisted of 138 total patients with 77 diagnosed with HAPE, 38 diagnosed with pneumonia, and 23 diagnosed with concomitant HAPE and pneumonia. Variables found to have no significance included gender, age, heart rate, and temperature. Variables with significance included respiratory rate, number of days ill, oxygen saturation, and chest x-ray findings. These significant variables were used to develop the Frisco Score. They do include a disclaimer that these findings are preliminary results on a small data set. Thus, as of yet, the Frisco Score should not be used on its own to make a diagnosis, but rather should be used as a clinical tool in differentiating conditions with similar presentations. 

Oxygen saturation varied greatly between patients with HAPE and those with pneumonia. Patients diagnosed with HAPE had an average oxygen saturation of 74% and those with pneumonia had an average of 92%. 

Patients who were diagnosed with HAPE had a higher average respiratory rate compared to those diagnosed with pneumonia.

 In patients diagnosed with HAPE, the duration of illness, or number of days ill, was shorter than those diagnosed with pneumonia. 

In comparison of chest x-rays, patients with HAPE were more likely to have diffuse findings and patients with pneumonia were more likely to have focal findings. 

Overall, there were no variables associated with a concomitant diagnosis of pneumonia and HAPE.

The asphalt road in the foreground leads past a sign for Common Spirit St. Anthony Summit Hospital just before the shelter over the entrance to a building labeled "ambulance" with deep green conifer forests stretching halfway up tall grey rocky mountains in the backgroundl.

In summary, patients diagnosed with HAPE had decreased oxygen saturation, increased respiratory rate, and diffuse findings on chest x-ray; while patients diagnosed with pneumonia had a longer duration of illness and focal findings on chest x-ray. The Frisco Score takes these variables into account to help differentiate a diagnosis of HAPE in children. Dr. Chris and Sean Finnegan, PA-C are currently presenting their findings at the 8th World Congress on Mountain and Wilderness Medicine in Snowbird, Utah. They hope that in the near future, the Frisco Score will be used to facilitate the diagnosis of HAPE by providers in high altitude communities state-wide.

References

1. Ebert-Santos, C. (2017). High-Altitude Pulmonary Edema in Mountain Community Residents. High Altitude Medicine & Biology, 18 (3), 278-284. https://doi.org/10.1089/ham.2016.0100

2. Ebert-Santos, C., Finnegan, S. (2024). Differentiating Pneumonia & HAPE in Children.

Acclimation, Altitude Science, Doc Talk, Genetics, Health, High Altitude

RED FLAGS AT ALTITUDE: When Your Doctor Tells You Your Labs AreNormal But the Results in the Patient Portal Are Flagged

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It comes as no surprise that living at altitude can take some adjustment. Travelers visiting just for a quick ski trip recognize  immediately, sometimes even at Denver International Airport when first arriving at Colorado’s Mile High City at 5280 feet, that the air is “thinner” than where they might have journeyed from. That thinner air we all feel is due to our altitude living at 9,075 feet (2) here in Frisco, CO. Our bodies can feel the atmospheric changes even if we do not recognize them ourselves. As a point of reference, on the rather extreme side, the “death zone” that comes to mind when thinking of the behemoth Mount Everest, is any elevation of 26,247 feet and above (3), a  zone we might not be as familiar with is the deterioration zone which begins at a mere 15,000 feet (3). In this zone, the symptoms are variable, but  common manifestations are lethargy, weight loss, poor appetite, and irritability (4). Altitude experts identify 8,000 feet as the elevation where  symptoms such as headaches and pulmonary edema are more likely to manifest. The good and bad effects of altitude are proportional to the elevation and variable between individuals. For all of you ‘fourteener’ fanatics out there, including myself, this comes as a reminder that we are closer than we think to detrimental elevation in our atmosphere. With this  frame of reference fresh in our minds, let us take a closer look at how living in at the elevation of Frisco, Colorado at 9000 feet or the neighboring towns can affect our health. 

Mountain residents who have blood tests done commonly see “red flags” next to some lab values. In particular, the complete blood count, commonly referred to as CBC. To most of us, those red flags are an alarming indicator that something must be terribly awry but au contraire,  there is an explanation why we need not worry. For those of us living at altitude, there is a reduced atmospheric pressure, so although the fraction of oxygen in the air is still 21%, the molecules are further apart. Fewer oxygen molecules enter our lungs and bloodstream  delivering less oxygen to our tissues(5). Remember now, we are not living on top of Mount Everest, so we are not in any danger, because our bodies are doing behind-the-scenes work for us! Our bodies are adapting by increasing the amount of red blood cells, which carry oxygen in our blood, throughout our bodies so that every organ is being supplied with the good stuff! This is exactly why athletes come here to train, to get their bodies to produce more red blood cells so they can perform at their absolute best. After three months of life in the mountains, nearly everyone has elevated red blood cells, hemoglobin, hematocrit, and red cell indices such as the MCV, (mean corpuscular volume), MCHC (mean corpuscular hemoglobin content) and MCH (mean corpuscular hemoglobin). A “normal” hemoglobin in a man who lived for years in the mountains was a signal to his doctor that the patient was anemic and in fact turned out to have colon cancer.

A more immediate response to the low oxygen environment at altitude is an increase in respiratory rate. In an interview with physician experts on altitude Dr. Elizabeth Winfield and Dr. Erik Swenson on May 30, 2023, both think this is the reason there is often a red flag for the carbon dioxide (CO2) as low, usually 17 to 19 with 20 being normal.  Because this affects the acid base balance, the serum chloride ( Cl) may be slightly elevated, 107 to 108 instead of 106. Dr. Winfield also explains to her patients that fasting for labs may cause mild dehydration leading to a slightly higher BUN, blood urea nitrogen, a marker of kidney function.  Another physiological response to altitude is a lower plasma volume, which may cause slight elevation in the serum protein and albumin.

So when you doctor calls you and tells you your labs are normal, ask them to drill down and explain the red flags.  If you find out something new, please put a comment on our blog and share with the world! Few health care providers really understand all the changes in the human body living in hypobaric hypoxic (low pressure, low oxygen) environments.

References 

1. Image. https://ichef.bbci.co.uk/news/624/cpsprodpb/960F/production/_83851483_c0249925-red_blood_cells,_illustration-spl.jpg. 

2. Town of Frisco Colorado. (2023). Maps. https://www.friscogov.com/your-government/maps/. 

3. Lankford, H. V. (2021). The death zone: Lessons from history. Wilderness & Environmental Medicine, 32(1), pp. 114-120. https://doi.org/10.1016/j.wem.2020.09.002. 

4. West, J. C. (2013). Case law update. Legal liability in emergency medicine and risk management considerations. Journal of healthcare risk management: the journal of the American Society for Healthcare Risk Management, 33(1), pp. 53-60. 

5. Cabrales, P., Govender, K. and Williams, A.T. (2020), What determines blood viscosity at the highest city in the world?. J Physiol, 598: 3817-3818. https://doi.org/10.1113/JP280206

6. Image. https://cdn.allsummitcounty.com/images/content/5717_13913_Frisco_Colorado_Main_Street_lg.jpg

Acclimation, Alcohol at Altitude, Altitude Science, Athletic Training, Backcountry, Backpacking, Child Growth & Development, Exposure, Health, High Altitude, High Altitude Training & Fitness, Huts, Hyperbaric Therapy, Medicine, Mountaineering, Naturopathic Medicine, Sleep at Altitude, Summit Huts

HAFE: High-Altitude Flatus Expulsion

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Often, at high altitude we hear complaints of gas pain and increased flatus in our infant population. Parents often wonder, are we doing something wrong? Is my child reacting to breastmilk, or showing an intolerance to certain foods?  Actually there is another explanation for increased flatus and gas pain in the high-altitude region of Colorado. 

The term HAFE was coined by Dr. Paul Auerbach and Dr. York Miller and published in the Western Journal of Medicine in 1981. Their discovery began In the summer of 1980, when the two doctors were hiking in the San Juan Mountains of Colorado on a quest to summit three 14ers. During their ascent they noticed that something didn’t smell right! As the pair continued to emit noxious fumes, they began to put their scientific brains to work and discovered HAFE. The symptoms include an increase in frequency and volume of flatus, or in other terms an increase in toots! We all have familiarity in watching our bag of potato chips blow up when reaching altitude or our water bottle expanding as we head into the mountains. This reaction is due to a decrease in barometric pressure. Based on Boyle’s law, decreased barometric pressure causes the intestinal gas volume to expand, thus causing HAFE (Skinner & Rawal, 2019).

A graphic illustrating how Boyle's law works: the pressure of a gas increases as its volume decreases.

To my surprise, a gas bubble the size of a walnut in Denver, Colorado (5280 ft) would be the size of a grapefruit in the mountain region of Summit County, CO (8000+ ft)! Trapped gas is known to lead to discomfort and pain. The use of simethicone may have merit in mitigating the effects of HAFE. Simethicone works by changing the surface tension of gas bubbles, allowing easier elimination of gas. This medication, while benign, can be found over the counter and does not appear to be absorbed by the GI tract (Ingold, C. J., & Akhondi, H., 2022). 

While this phenomenon may not be as debilitating as high-altitude pulmonary edema (HAPE), it deserves recognition, as it can cause a significant inconvenience and discomfort to those it inflicts. As the Radiolab podcast explained in their episode The Flight Before Christmas , expelled gas in a plane or car when driving up to the mountains can be embarrassing. While HAFE can be inconvenient, it is a benign condition and a matter of pressure changes rather than a disease or pathological process. We would love to talk more about HAFE at Ebert Family Clinic if you have any questions or concerns!

A bald eagle flies over a misty settled into the valley against the blue-green pine forest of a mountain.
A bald eagle flies toward its nest atop a bare lodgepole pine.

As always, stay happy, safe, and healthy 😊

Taylor Hollingsworth is finishing her final semester as a family nurse practitioner (FNP) student at Georgetown University. Originally from the east coast, Taylor plans to start her FNP career in North Carolina close to family. She has a passion for pediatric and family wellness and has worked as a pediatric intensive care unit nurse for 6 years! In her free time, Taylor loves to hike, fly fish, run, and spend time with her fiancé Logan. 

References

Auerbach, P. & Miller, Y. (1981). High altitude flatus expulsion. The Western Journal of Medicine, 134(2), 173-174.

Chemistry Learner. (2023). Boyle’s Law. https://www.chemistrylearner.com/boyles-law.html

Ingold, C. J., & Akhondi, H. (2022). Simethicone. StatPearls Publishing. 

McKnight, T. (2023). The Flight Before Christmas [Audio podcast]. Radiolab. https://radiolab.org/episodes/flight-christmas

Skinner, R. B., & Rawal, A. R. (2019). EMS flight barotrauma. StatPearls Publishing. 

Acclimation, Altitude Science, Backpacking, Child Growth & Development, Doc Talk, Exposure, Genetics, Health, High Altitude, High Altitude Training & Fitness, Medicine

Re-Entry HAPE: Leading Cause of Critical Illness in Mountain Teens

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Health care providers and people who live at altitude often believe that living in the mountains protects from altitude related illness. And yes, there are many ways the body acclimatizes over days, weeks, months, and years, as addressed in previous blog entries. However, as a physician who has practiced in high altitude communities for over 20 years, my personal observation that we are still at risk for serious complications was reenforced by a recent publication by Dr. Santiago Ucrós at the Universidad de los Andes School of Medicine in Santa Fe de Bogotá, Colombia. His article, High altitude pulmonary edema in children: a systemic review, was published in the journal Pediatric Pulmonology in August 2022. He included 35 studies reporting 210 cases, ages 0-18 years, from 12 countries.

A chart titled "HAPE in Children" illustrates cases of high altitude pulmonary edema by country.

Consistent with our experience in Colorado, the most common ages were 6-10 years and second most common 11-15 years. I have not seen or read any reports of adults affected. Cases included two deaths, which I have also seen here.

I receive reports on any of my patients seen in urgent or emergency care. Accidents, avalanches, and suicide attempts are what we think of first needing emergency care in the mountains. However, the most common critical condition is Reentry HAPE. This is a form of pulmonary edema that can occur in children who are returning from a trip to lower altitude. Think visiting Grandma during school break.  Dr. Ucrós’ review also confirms that all presentations of HAPE (classic, as in visitors, reentry, and HARPE, resident children with no history of recent travel) are more common in males by a 2.6 to 1 ratio. Analysis of time spent at lower altitude before the episode showed a range of 1.6 to 30 days with a mean of 11.3 days. Mean time between arrival and onset of symptoms for all types of HAPE was 16.7 hours. The minimum altitude change reported in a HAPE case was 520 meters (1700 feet), which is the difference between Frisco, CO (Summit County) and Kremmling, CO (Grand County, the next county over). A new form of HAPE in high altitude residents who travel to higher altitude was designated HL-HAPE in this review.  A case report will be featured in an upcoming blog interview with a Summit County resident who traveled to Mt. Kilimanjaro.

As with all cases of HAPE, the victims develop a cough, sound congested as the fluid builds up in their lungs, have fatigue, exercise intolerance, with rapid onset over hours of exposure to altitude, usually above 8000 ft or 2500m. Oxygen saturations in this paper ranged from 55 to 79%. My patients have been as low at 39% in the emergency room.  Children presenting earlier or with milder cases come to the office with oxygen saturations in the 80’s. An underlying infection such as a cold or influenza is nearly always present and considered a contributing factor. Everyone living or visiting altitude should have an inexpensive pulse oximeter which can measure oxygen on a finger. Access to oxygen and immediate treatment for values under 89 can be life-saving.

The recurrence rate for all types of HAPE is about 20%. Most children never have another episode, but some have multiple. Preventive measures include slower return to altitude, such as a night in Denver, acetazolamide prescription taken two days before and two days after, and using oxygen for 24-48 hours on arrival. Most families learn to anticipate, prevent, or treat early and don’t need to see a health care provider after the first episode.

On January 26, 2023 I met with Dr. Ucrós and other high altitude scientists including Dr. Christina Eichstaedt, genetics expert at the University of Heidelberg in Germany, Dr. Deborah Liptzen, pediatric pulmonologist, and Dr. Dunbar Ivy, pediatric cardiologist, both from the University of Colorado and Children’s Hospital of Colorado, and Jose Antonio Castro-Rodríguez MD, PhD from the Pontifica Universidad Católica in Santiago de Chile.

We discussed possible genetic susceptibility to HAPE and hypoxia in newborns at altitude with plans to conduct studies in Bogotá and Summit County, Colorado.

Acclimation, Altitude Science, Athletic Training, Child Growth & Development, Doc Talk, Exposure, Health, High Altitude, High Altitude Training & Fitness, Medicine, Mountaineering

Going Home to the Mountains Can Be Dangerous: Re-Entry HAPE (High Altitude Pulmonary Edema)

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Louie was excited to get out on the slopes after spending Thanksgiving with family in Vermont. He got tired early and felt his breathing was harder than usual, leaving early to go home and rest. As a competitive skier he thought that was strange. But he was getting over a cold. He could not have imagined that in 24 hours he would be in the emergency room, fighting for his life.

Louie experienced a dangerous condition, set off by altitude, and inflammation from his “cold”, that caused his lungs to fill with fluid.  His oxygen saturation was 54 % instead of the normal 92, he had been vomiting and feeling very weak and short of breath. His blood tests showed dehydration, hypoxemia and acute kidney injury. His chest x-ray looked like a snowstorm. He was transferred to Children’s Hospital in Denver and admitted to the intensive care unit.

The diagnosis of Re-entry HAPE was confirmed by echocardiogram showing increased pressures in his lungs. He improved rapidly with oxygen and low altitude.

Re-entry HAPE is not rare, affecting several Summit County children every year.  Many do not come to medical attention because after their first episode parents carefully monitor their oxygen and have a concentrator available in their home when they return from travel. 

Medical providers may not be aware of this risk, expecting that children living at altitude are acclimatized. (See previous blog entry on Acclimatization vs. Adaptation, April 17, 2019) Re-entry HAPE seems to occur mostly in children between the ages of 4 and 15. Inflammation, such as a viral respiratory infection, seems to play a role.  Trauma may also predispose a returning resident to Re-entry HAPE, as described in our blog post from February 5, 2018, Re-entry HAPE in High Altitude Residents.

Louie agreed to share his story on our blog to help educate medical personnel and families living in the mountains about this dangerous condition. Further research will help define who is at risk.  The University of Heidelberg recently published an article on the genetics of pulmonary hypertension (HARPE is the New HAPE) and is interested in testing families here who have had more than one person affected by HAPE.

Acclimation, Altitude Science, Child Growth & Development, Doc Talk, Exposure, Health, High Altitude, Medicine

HARPE is the New HAPE

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It took ten years for me to convince high altitude experts that children living in the mountains get high altitude pulmonary edema (HAPE) without leaving home. My observations were published in 2017 in the Journal of High Altitude Medicine and Biology,

High-Altitude Pulmonary Edema
in Mountain Community Residents

This week Dr. Jose A Castro-Rodriguez MD PhD ATSF discussed HAPE in children at the 8th World Hypoxia conference in La Paz including the now renamed high altitude resident pulmonary edema (HARPE) in his presentation.

Dr. Castro-Rodriguez emphasized the importance of recognizing the three forms of HAPE, including reentry HAPE when children return to the mountains from vacation, since these can be life threatening.

My work has been cited in articles by pulmonologists Deborah Liptzin and Dunbar Ivy from Children’s Hospital of Colorado and geneticist Christine Eichstaedt and her team at the University of Heidelberg.

At Ebert Family Clinic we give every patient/family a free pulse oximeter. The ability to measure the oxygen saturation of anyone with cough, congestion, or fatigue can facilitate early treatment with oxygen and prevent visits to the emergency room, hospital and intensive care unit.

I recently received first prize for a poster presentation on HARPE at the fall Colorado Medical Society meeting, and second prize for a poster on Trauma and HAPE.

For more information about HAPE, HARPE and Trauma-related HAPE, see previous blog entries.

References

Ebert-Santos C. High-Altitude Pulmonary Edema in Mountain Community Residents. High Alt Med Biol. 2017 Sep;18(3):278-284. doi: 10.1089/ham.2016.0100. Epub 2017 Aug 28. PMID: 28846035.

Giesenhagen AM, Ivy DD, Brinton JT, Meier MR, Weinman JP, Liptzin DR. High Altitude Pulmonary Edema in Children: A Single Referral Center Evaluation. J Pediatr. 2019 Jul;210:106-111. doi: 10.1016/j.jpeds.2019.02.028. Epub 2019 Apr 17. PMID: 31005280; PMCID: PMC6592742.

Liptzin DR, Abman SH, Giesenhagen A, Ivy DD. An Approach to Children with Pulmonary Edema at High Altitude. High Alt Med Biol. 2018 Mar;19(1):91-98. doi: 10.1089/ham.2017.0096. Epub 2018 Feb 22. PMID: 29470103; PMCID: PMC5905943.

Eichstaedt CA, Mairbäurl H, Song J, Benjamin N, Fischer C, Dehnert C, Schommer K, Berger MM, Bärtsch P, Grünig E, Hinderhofer K. Genetic Predisposition to High-Altitude Pulmonary Edema. High Alt Med Biol. 2020 Mar;21(1):28-36. doi: 10.1089/ham.2019.0083. Epub 2020 Jan 23. PMID: 31976756.

Acclimation, Altitude Science, Health, High Altitude, Medicine

The Nobel Prize: Hypoxia studies Won in 2019!

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The Nobel prizes are announced this month. Alfred Nobel invented dynamite in 1866. Within 30 years, Nobel made a large fortune from his invention. He demonstrated his passion for literature and science by creating a yearly prize to discoveries most beneficial to humankind. The five prize categories include physics, chemistry, medicine (physiology), literature and peace. The Nobel prize nominations are made by university professors, national assemblies, state governments, and international courts. The prize is awarded yearly to individuals who have discovered a new paradigm or a paradigm shift within their field. The prize recipients are declared on the first Monday of October of every year and the award is presented by the Nobel assembly on November 10th, the anniversary of Alfred Nobel’s death. The Nobel prize consists of a gold medal, a diploma of recognition of achievement, and a cash prize in the amount of $1 million U.S. dollars. 

There is no limit to the number of nominations that can be made or the number of times that an individual can be nominated. There were 400 candidates nominated in the field of medicine in 2019, all of which inspired, challenged, and demonstrated greatness in their field. In 2019 the Nobel Prize in Medicine honored three scientists for their discovery of the human body’s ability to adapt to low oxygen environments. 

Hypoxia is a state of which oxygen supply is insufficient for normal life functions, experienced by the human body at high altitude. Tissues and cells require a range of oxygen in order to survive. Oxygen is required by mitochondria, in all cells, to convert food into useable energy. “Otto Warburg, the recipient of the 1931 Nobel Prize in Physiology or Medicine, revealed that this conversion is an enzymatic process.” At low oxygen environments, as experienced at high altitude, the body must adapt in order to maintain basic cellular function. There are several mechanisms in the human body that increase oxygen concentration including breathing rate, regulated by the carotid body, increased heart rate, stimulated by the vagus nerve, and increased production of red blood cells (RBCs)  through the bone marrow, regulated by the kidney. 

The carotid body is a chemoreceptor near the carotid artery that detects oxygen, carbon dioxide and pH levels in the blood. At low oxygen, the carotid body relays an afferent (ingoing) signal to the the brain via the glossopharyngeal nerve. The medullary center in the brain then sends an efferent (outgoing) signal that increases the respiratory rate to maximize oxygen delivery to the brain. The carotid sinus is a baroreceptor near the aorta of the heart which senses changes in pressure. As pressure increases in the atmosphere, experienced at high altitude, the carotid sinus sends a signal along the vagus nerve to the brain which then increases the heart rate. “The 1938 Nobel Prize in Physiology or Medicine was awarded to Corneille Heymans for discoveries showing how blood oxygen sensing via the carotid body controls our respiratory rate by communicating directly with the brain.”

At low oxygen environments, the kidney increases production of erythropoietin, which stimulates RBC generation in the bone marrow,  called erythropoiesis, resulting in higher oxygen delivery to the brain and skeletal muscles needed at high altitude. Erythropoiesis was discovered in the early 20th century, however oxygen’s role in the process was not completely understood. The cell’s ability to sense and adapt to oxygen availability was discovered and explained by three scientists, William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza. 

2019 Nobel Prize, Physiology: 

Thanks to the work of Dr. Gregg L. Semenza and Sir Peter J. Ratcliffe, we now understand that the oxygen sensing mechanism that stimulates erythropoieten is present in all tissues, not just the kidney. Semenza conducted research on liver cells using gene-modified mice and found that a specific protein binds to an individual gene (the EPO gene), dependent upon oxygen availability. Semenza named the binding protein the Hypoxia-Inducible-Factor (HIF). The HIF protein was found to compose two transcription factors, HIF-1alpha and ARNT. In 1995, Semenza published his findings of the HIF protein. His work explained that when the body is at high oxygen environments, there is very little HIF-1alpha present within cells. At high oxygen availability, HIF-1alpha is rapidly degraded by a proteasome within cells. The degradation is signaled by a protein called ubiquitin which binds to HIF-1alpha at high oxygen, flagging HIF-1alpha for degradation by the proteasome. This process was recognized by the 2004 Nobel Prize in Chemistry, Aaron Ciechanover, Avram Hershko and Irwin Rose. 

The mechanism by which ubiquitin binds, causing the degradation of HIF-1alpha at high oxygen environments was explained by the work of William Kaelin, Jr. who conducted research on von Hippel-Lidau’s (VHL) disease. The VHL gene mutation causes an increased risk of cancer. Kaelin showed that the VHL gene encodes a protein that prevents the onset of cancer and was involved in controlling responses to hypoxia. VHL is part of a complex that labels proteins with ubiquitin. Ratcliffe discovered the physical interaction of the VHL gene with HIF-1alpha, causing degradation of the HIF-1alpha at normal oxygen levels. 

At hypoxic environments, HIF-1α is protected from degradation and accumulates in the nucleus, where it associates with ARNT and binds to specific DNA sequences (HRE) in hypoxia-regulated genes (1). At normal oxygen levels, HIF-1α is rapidly degraded by the proteasome (2). Oxygen regulates the degradation process by the addition of hydroxyl groups (OH) to HIF-1α (3). The VHL protein can then recognize and form a complex with HIF-1α leading to its degradation in an oxygen-dependent manner (4). 


At hypoxic environments, HIF-1α is protected from degradation and accumulates in the nucleus, where it associates with ARNT and binds to specific DNA sequences (HRE) in hypoxia-regulated genes (1). At normal oxygen levels, HIF-1α is rapidly degraded by the proteasome (2). Oxygen regulates the degradation process by the addition of hydroxyl groups (OH) to HIF-1α (3). The VHL protein can then recognize and form a complex with HIF-1α leading to its degradation in an oxygen-dependent manner (4).

Kaelin and Ratcliffe’s research identified how oxygen levels regulate the interaction between VHL and HIF-1alpha. Their work demonstrated that at normal oxygen levels, hydroxyl groups are added to specific positions within HIF-1alpha, causing modification of the protein and allowing VHL to recognize and bind to HIF-1alpha, leading to degradation of the protein complex.  At high altitude, cells produce a greater amount of the HIF-1alpha protein which binds to the EPO gene, up-regulating the production of erythropoietin hormone, stimulating RBC production. Together, Semenza, Kaelin, and Ratcliffe explained the oxygen sensing mechanism.